Dienoic acid amides



United States Patent 3,173,942 DIENOIC ACID AMIDES Derek H. R. Barton, London, England, and Gerhard Quinkert, Braunschweig, Germany, assignors to Polaroid Corporation, Cambridge, Mass, a corporation of Delaware No Drawing. Filed Jan. 19, 1962, Ser. No. 167,417 Claims priority, application Great Britain, July 23, 1958, 23,753/ 58 6 Claims. (Cl. 260490) This invention is concerned with a new process for the production of unsaturated hydrocarbon derivatives.

It has been found according to the invention that a novel diene acid or a derivative thereof of the formula:

in which R R R R R and R are alkyl, alltoxy, acyl, alkenyl, aralkyl, aralkenyl or aryl groups or halogen or hydrogen atoms may be prepared by the irradiation with ultraviolet light in the presence of a nucleophilic reagent of the formula HX of a 6,6-disubstitutexl cyclohexadienone of the formula:

(I in which R R R R R and R may have the same meanings as above.

Reagents of formula HX which are suitable for use in the present reaction include water, primary and secondary amines, alcohols and acids. Thus when the reaction is carried out in the presence of water, adiene acid is formed whereas in the presence of an amine the corresponding amide is formed and in the presence of an alcohol, the corresponding ester.

Particular reagents which have been found suitable include water, aniline and vcyclohexylamine.

The reaction according to the invention is preferably carried out in the presence of an inert solvent, e.g., ether. However, when the starting material is sufiiciently soluble in the reagent HX a solvent will in general be unnecessary.

The quantity of water, amine or alcohol present in the reaction should, of course, preferably be at least stoichiometrically equivalent to the amount of cyclohexadienone, advantageously in considerable excess.

It is preferred to carry out the reaction in dilute solutions of the cyclohexadienone concentrations of the order of 0.1% often being found convenient.

In general it is advantageous if the irradiation is carried out in the absence of air in an atmosphere of an inert gas, for example, nitrogen.

The time of irradiation required for the reaction varies with the intensity and wavelength of the radiation, the quantity of the starting material and the absorption of the vessels containing the cyclohexadienone solution. However, since the U.V. absorption spectrum of the diene acid varies very considerably from that of the cyclohexadienone, the course of the reaction can easily be followed and be stopped when the UV. absorption spectrum of the solution ceases to change or at a convenient subse- $373,942 Patented Mar. 16, 1965 quent time. For maximum efiiciency of irradiation the vessels containing the solution should be of a substance which absorbs little U.V. radiation, for example, quartz rather than glass.

The Wavelength of the radiation is advantageously that at which maximum absorption takes place by the cyclohexadienones; the light used should thus have substantial intensity at wavelengths between 250 and 500 III/L, preferably around 300 Inn.

The temperature of the solution does not appear to aifect the course of the reaction and may be varied widely. It is generally convenient to irradiate at approximately room temperature or, sometimes, at the boiling point of the solution. Naturally the heating effect of the radiation tends to raise the temperature of the solution.

The 6,6-disubstituted cyclohex adienones used as starting materials may be prepared in any convenient manner. One method which is particularly suitable and which has rendered such 6,6-disubstitnted cyclohexadienones gen enally available, is oxidation of phenols with lead tetraacetate by the method of Wessely (Monatsch, 1950, 81, p. 1066, and 1954, 85, p. 69).

It appears that the reaction passes through a ketene intermediate by a reversible electron rearrangement.

The ketene compound IV then reacts with the nucleophilic reagent to form the diene acid I. In certain cases the form I of dieneacid is isomerised into the acid II. This isomer is preferred when 1,3 interaction occurs between the groups R and R or R or both, the form II of the acid having such non-bonded interaction at a minimum.

It is also pointed out that when irradiating a compound of Formula III in which R is a group other than hydrogen and R and R are groups which will interact with the group R a strong nucleophilic reagent should be used. The trans form of ketene IV which reacts with the nucleophilic reagent is stereochemically untavoured because of the 1,3 interactions and there is a high rate of back reaction to the starting material. A nucleophilic reagent should therefore be used which will react with the ketene at a higher rate than the rate of the back reaction. Cyclohexylamine has been found suitable as a nucleophilic reagent for use with such compounds.

The new diene acids and their carboxylic derivatives produced according to the present process are useful as intermediates in organic synthesis. Where one of groups R and R is an acyloxy group, acid or alkaline hydrolysis gives rise to an enolic hydroxyl group which rearranges to give an alphazbeta-unsaturated ketone. One particularly interesting synthesis made possible by the present process is the production or" the carotenoid crocetin by irradiation of a l,4-di-6-( l-keto-2,6-dimethyl-4-halo-cycloheXadiene-2,4-yl)-but-2-ene in ether saturated with water, followed by dehydrohalogenation of the resulting dihalo dicarboxylic acid with, for example, collidine. Since the starting material may be prepared by reaction of a 2,6- dimethyl-4-halophen0l with a 1,4-dihalo-but-2-one by the method of Curtin, Crawford and Wilhelm (J.A.C.S., 1958, 80, 1891) and since 2,fi-dimethyll-halophenols are simply prepared by direct halogenation of the commercially available 2,6-dimethyl phenol, the process according to the present invention affords a particularly direct method of synthesizing crocetin. In general, in fact, the process of the present invention represents a valuable new method of splitting the phenyl ring without resource to the rigorous treatment which is usually necessary.

The process also has photographic application as exposure of a compound of Formula 111 to ultraviolet light in the presence of water causes the formation of an acid which could be used to neutralize the alkaline developing agent and stabilize the image.

The structure of the new diene'acids produced by the present process has been established by degradative experiments and by examination of the ultraviolet spectra of the compounds. Thus the cyclohexadienone of Formula X in which R is a methyl group, R is an acetyloxy group and R R R and R represent hydrogen atoms on irradiation gave a diene acid which on hydrogenation took up 2 mols. of hydrogen to give an oily tetrahydro-acid. Saponification of the acetyloxy group of this tetrahydroacid and chromic acid oxidation of the resulting hydroxy acid gave a keto-acid which on methylation with diazomethane gave a keto acid ester characterized, by means of its 2,4-dinitrophenyl-hydrazone, as methyl 5-keto-hex ane-l-carboxylate CH CO(CH COOCH (V). (Schaefier and Snoddy, Organic Syntheses, 1951, 85, 69.)

Since none of these steps would be expected to cause any rearrangement of the molecule, the diene acid investigated must have possessed an acetyloxy group in place of the keto group of Formula V, a free carboxyl group in place of the ester group and two carbon-carbon double bonds.

The infrared spectrum of the same diene acid corresponded exactly to that theoretically predicted from the postulated structure of the acid, showing, in particular that the double bonds were conjugated and that the acetyloxy group was enolic in nature.

phenacyl ester, MP. 59-60 C. This ester analyzed as follows:

Theoretical C, 53.3; H, 5.5; Er. 20.75. 53.55; H, 5.9; Br. 20.65. a

The pure product on reaction with methanolic hydrochloric acid and 2,4-dinitrophenylhydrazine gave the 2,4- dinitrophenyl-hydrazone of 1-acetyl4-carboxymethyl butl-one, Mr. 119 120 0., r (EtOH) 374 mu,

Analysis-Theoretical C, 50.00; H, 4.80; N, 16.66. Found: C, 50.19; H, 4.84; N. 17.13.

EXAMPLE ll Irradiation of 6,6-dimethylcyclohexa-Z,4-dien-1-0ne 6,6-dimethylcyclohexadienone (330 mg.) in ether (330 ml.) saturated with water was irradiated for 3 hours. The crude product (356 mg.86.5% theoretical yield) was crystallized from light petroleum (B.P. 6080) and gave 6-methylheXa-3,5-dien0ic acid (244 mg.64% theoretical) k 238, e =23,500, M39. 4850 C.

Analysis.-Theoretical: C, 68.5; H, 8.6.

Found C,

Found: C,

It gave acetone (44%) on ozonolysis.

Found: C, 57.3; H, 5.5; Br, 23.9,.

The invention will now be illustrated by the following examples. The following general procedure was adopted: The irradiations were carried out under oxygen-free nitrogen in a Pyrex flask by a mercury vapour lamp (250 at the of the Solvsnt- The flask was placed at with water was irradiated for 2.5 hours. The crude prod- 10 cm. from the light source. The concentration of the solutions used was between 0.1 and 1% in cyclohexadienone. Aliquots were removed at 30 min. (or shorter if more convenient) intervals for ultraviolet absorption measurement. When there was no further change the reaction mixture was irradiated for a further 30 mins. and then worked up. In every case a blank experiment was carried out at the time under exactly the same conditions but without irradiation. It was shown by ultraviolet absorption measurements as well as by the appropriate isolation of starting material that in no case was there any chemical reaction from purely thermal causes. In each case the heat from the mercury lamp caused the ethereal solvent to reflux.

EXAMPLE I Irradiation of 6-acet0xy-6-methylcycl0hexa-2,4-dien-1-one in the presence of water The cyclohexadienone (1.24 g.) in other (1240 m1.) previously saturated with water, was irradiated for three hours. The dried (MgSO ethereal solution was evaporated and the residue crystallized twice from cyclohexane to give 6-acetoxyhepta-3,S-dienoic acid.

Characteristics of crude product: Yield 1.31 g.93.5% theoretical. k =234.5 m e=23,400.

Characteristics of purified product: Yield 1.09 g.79% theoretical. k =235 mu, e=23,800.

Analysis.-F0und C, 58.95; H, 6.75. 58.7; H. 6.55.

Infrared spectrum (in CI-lCl 3480 (monomeric hydroxyl group), 34-40-2500 (associated hydroxyl of carboxylic acid group), 1748 (enolic acetate), 1726 (saturated carboxyl group) and 1677 and 1622 (conjugated ethylenic linkages) cmr' Hydrogenation (2 mols. uptake) gave an oily tetrahydro-acid characterized as the p-bromo- The p-bromophenacyl ester of the pure product was prepared, MP. 108-108.5 C. Analysis-Theoretical: C,

57.0; H, 5.1; Er. 23.7.

EXAMPLE III Irradiation of 6,6 -diacetoxy-4-methylcyclohexa- 2,4-dien-1-0ne The dienone (510* mg.) in ether (510 ml.) saturated EXAIVHLE IV v Irradiation of 6-acet0xy-6-methyl cyclohexn-2,4-dien-I- one in the presence of organic bases (a) Aniline.Thedienone (543 mg.) and redistilled aniline (614 mg.) in dry ether (540 ml.) were irradiated for 100 mins. Removal of the excess of aniline by shaking with 4 N aqueous hydrochloric acid and working up Required C, V

in the usual way gave the anilide of 6-acetoxyhepta-3,5- dienoic acid. Purified by filtration in benzene solution over silica gel (5 g.) and crystallization from aqueous ethanol this (670 mg.) had M.P. 105106, k 245m, (e =33,400),infrared bands (in CHCl at 3384 (secondary amide group), 1755 (enol acetate) and 1682 (anilide carbonyl) emf- (Found: C, 69.7; H, 6.7; N, 5.25. C15H17O3N requires C, 69.5; H, 6.6; N, 5.4%.)

' (b) Cycl0hexylamine.-The dienone (1.22 g.) and cyclohexylamine (1.51 g.) in dry other (800 ml.) were irra-' diated for two hours. The excess of cyclohexylamine was removed as above and the reaction product isolated in the usual way. Recrystallization from ether gave the cyclohexylamide of 6-acetoxyhepta-3,S-dienoic acid (1.55 g.), M.P. (white needles) 86.5 88", A 237m (e=23,900), infrared bands (in CC1 at 3389 (secondary amide group), 1759 (enol acetate) and 1670 (cyclohexylamide carboxyl) cmr (Found: C, 67.85; H, 8.6; N, 5.3.

C H O N requires C, 67.9; H, 8.75; N, 5.3%.)

EXAMPLE V Irradiation of -ncetoxy-4,6-dimethylcyclohexa- 2,4-dien-l-one (a) The dienone (750 mg.) in anhydrous ether (750 ml.) containing cyclohexylamine (836 mg.) was irradiated for 4 hours. After removal of the cyclohexylamine with 3 N aqueous hydrochloric acid, the product was fil tered in light petroleum through silica gel (15 g.) and then crystallized from light petroleum to give the cyclohexylamide of 6-acetoxy-4-methylhepta-2,5-dienoic acid (1.09 g.; 81%), MP. 52-54, and the absorption at 210111;]. (e=4,500), infrared bands (in CCl at 3379 (secondary amide group), 1749 (enol acetate), 16.78 (amide carboxyl) and 1225 (enol acetate) cmf (Found: C, 68.8; H, 8.9; N, 5.05. 1-1 0 requires C, 68.8; H, 9.0; N, 5.0%.)

EXAMPLE VI Irradiation of 6-zzcet0xy-2,6-dimethylcyclohexa- 2,4-dien-1-one The dienone (635 mg.) in dry ether (635 ml.) containing cyclohexylamine (819 mg.) was irradiated for two hours. The excess of cyclohexylarnine was removed as before and the product (in benzene) was filtered through siiica gel (5 g.) to give the cyclohexylamide of 6-acetoxyhepta-3,S-diene-Z-carboxylic acid (906 mg.; 82%). Recrystallized from light petroleum Bl. 60-80", this had M1. 134-135", A 238m (-e=23,100), infrared bands at 3360 (secondary amide), 1755 (enol acetate) and 1672 (amide carbonyl) cmf (Found: C, 68.5; H, 9.2. C I-1 0 11 requires C, 68.8; H, 9.0%.)

EXAMPLE VII Irradiation of 6-allyl-2,6-dimethylcycl0hexa- 2,4-dien-1-one The crude dienone 18 (530 mg.) in dry ether (550 ml.) containing cyclohexylamine (3 ml.) was irradiated for three hours. Removal of excess cyclohexylamine and chromatography over alumina (Grade III; 350 g.) gave, on elution with light petroleum-ether (8:2) a main fraction having A 245111;: (e=18,000). Rechroniatography then furnished the cyclohexylamide of 6-methylnona-3,5, 8-triene-2-carhoxylic acid (216 mg). Recrystallized from light petroleum this had MP. 79-81", A 245mg (e=25,2()0) infrared bands (in CCl at 3390 (secondary amide group), 1670 (amide carbonyl) and 910 and 990 (vinyl group) cm.- (Found: C, 78.05; H, 10.2; N, 5.4. C H ON requires C, 78.1; H, 10.4; N, 5.35%.)

EXAMPLE VIII lrradialion of 6-ncei0xy-2,4,d-trimet/zyl-cyclohexa- 2,4-dien-1-0ne The dienone (1.19 g.) in anhydrous ether (550 ml.) containing cyclohexylamine 1.19 g.) was irradiated for two hours. The solvent and excess of cyclohexylamine were removed in vacuo and the product filtered in light petroleum through silica gel (150 g.) to give the cyclohexylamide of 6-acetoxy-4-methylhepta-2,5-diene-2-carboXylic acid (1.51 g.; 84%). Recrystallized from light petroleum (998 mg), this had M.P. 76-79, (shoulder) 219-225 m (5:3,000) infrared bands (in OCl at 6 3363 (secondary amide), 1745 (enol acetate), 1678 (amide carbonyl) and 1230 (enol acetate) cmr (Found: C, 69.4; H, 9.1; N, 4.8. C1qH27O N requires C, 69.6; H, 9.4; N, 4.75%.) This amide took up rapidly 1.9 mole. of hydrogen on microhydrogenation over platinum in ethyl acetate solution.

EXAMPLE IX Irradiation 0 6-allyl-2,4,6-trimethylcyclohexa-2,4- dien-l-one The dienone (2.84 g.) in anhydrous ether (500 ml.) containing cyclohexylamine (3 ml.) was irradiated for 13.5 hours. The excess of cyclohexylamine was removed as before to give an oil (2.88 g.). A portion (840 mg.) of this product was chromatographed in light petroleum over acid silica gel. Elation with 5:1-1ight petroleumether gave the cyclohexylamide of 4,6-dimethylnona-2,5, 7-triene-2-carboxy1ic acid (615 mg.; 83.5%) which crystallized on standing. Recrystallized in the cold from light petroleum this had M.P. 50-53", A 210 my (end absorption) (=12,300), infrared bands (in CCl at 3358 (secondary amide group), 1673 (amide carbonyl) and 916 and 982 (vinyl grouping) cmr (Found: C, 78.65; H, 10.3. C H ON requires C, 78.8; H, 10.3%.)

This application is a continuation-in-part of our copending application, Serial No. 828,688, filed July 22, 1959, now US. Patent No. 3,032,491, issued May 1, 1962.

What is claimed is:

1. An amide selected from the group consisting of anilides and cyclohexylamides of a diene acid of the formulae:

P! in n and References Cited in the file of this patent UNITED STATES PATENTS Barton et al. May 1, 1962 OTHER REFERENCES Kuhn et al.: Ber. Deut. Chem, vol. 65, pp. 172-3 (1932).

Kuhn et al.: Beilstein (Handbuch, 4th ed.), vol. 4, 3rd Sup., p. 1467 (1961). 

1. AN AMIDE SELECTED FROM THE GROUP CONSISTING OF AMILIDES AND CYCLOHEXYLAMIDES OF A DIENE ACID OF THE FORMULAE: 